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CN1224012A - Process for production of alpha-tocopherol esters - Google Patents

Process for production of alpha-tocopherol esters Download PDF

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Publication number
CN1224012A
CN1224012A CN98125686A CN98125686A CN1224012A CN 1224012 A CN1224012 A CN 1224012A CN 98125686 A CN98125686 A CN 98125686A CN 98125686 A CN98125686 A CN 98125686A CN 1224012 A CN1224012 A CN 1224012A
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acid
tmhq
acetate
reaction
vitamin
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CN1136211C (en
Inventor
斯特芬·克里尔
弗朗克·许布纳
赖纳·哈恩
霍斯特·魏格尔
克劳斯·胡特马赫尔
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Evonik Operations GmbH
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Degussa GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrane Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

The present invention relates to a process for the production of alpha -tocopherol esters, derivatives and homologs thereof of the general formula in which the mono- or diester of a hydroquinone is reacted with an allyl alcohol derivative or an allyl alcohol in the presence of zinc halides and proton-liberating acids at a temperature of 25 DEG to 100 DEG C.

Description

The method for preparing alpha-tocopherol esters
The present invention relates to the preparation of α-DL-Renascin (vitamin-e ester), its derivative and analogue, it is to make diacetylation replace quinhydrones and phytol and isophytol or its analogue in the presence of the compound of catalytic activity to react having.
Known method mainly is preparation α-DL-tocopherol.Alpha-tocopherol and its derivative mainly are medicament and the related application that is used for fodder additives, oxidation inhibitor, the sanguimotor medicament of stimulation, reduces cell senescence.
According to prior art, normally use Trimethylhydroquinone (TMHQ) as initiator, make this material and isophytol reaction (DE-OS 4243464=US-PS5,523,420, DE-OS19603142, EP0694541) with various catalyst systems.After reaction is finished, must fully make the product acetylize immediately, to obtain the vitamin e acetate of for example conventional commercially available stable storing.The common trait of all these methods is that they directly do not produce VITAMIN E ACETATE--the form of conventional commercially available, the stable storing of vitamin-E.
Also attempt by making Trimethylhydroquinone ester and isophytol react synthetic tocopherol as educt.FR-A2259822 (DE-OS2404621) relates to use diacetylation Trimethylhydroquinone.But, wherein describe only to form productive rate with the condensation reaction of isophytol in the presence of solid acid be α-DL-tocopherol of about 41%, and do not produce corresponding ester.
DE-OS2160103 (=US-PS3,789,086) has described the condensation reaction of Trimethylhydroquinone monoacetate and isophytol.Use Fe (II) Cl 2Water with in hydrochloric acid and the while separating reaction only forms alpha-tocopherol acetate in a small amount, and must carry out the back acetylize with amine catalyst and the diacetyl oxide that adds the hyperstoichiometry amount.
According to JP-OS51-80859 (on July 15th, 196), in the presence of zinc chloride, make the reaction of Trimethylhydroquinone or its ester and isophytol.According to the document, reaction forms alpha-tocopherol when surpassing 100 ℃.
The improved method that the purpose of this invention is to provide a kind of α of preparation-DL-Renascin wherein, is reflected in the fs and carries out to the direction that forms ester as much as possible.
The invention provides a kind of method for preparing alpha-tocopherol esters, derivative or the analogue of following logical formula I,
Figure A9812568600061
The method is characterized in that, at zinc halide, when releasing protonic acid and water and existing, under 25-100 ℃, preferred 40-80 ℃, the quinhydrones monoesters or the diester of logical formula II
Figure A9812568600062
Wherein: R 1, R 2Represent branch or not branched C 1-C 20Alkyl, R 1Be different from R 2Perhaps R 1=R 2
R 3, R 4, R 5Represent H, C 1-C 3Alkyl, their allyl alcohol derivative reactions identical or different and logical formula III,
Figure A9812568600071
Wherein: n represents the number of 0-5, and L representation hydroxy, halogen, acetoxyl group, mesyloxy, ethanesulfonyloxy group, phenylsulfonyloxy or tosyl group, perhaps the vinyl carbinol with logical formula IV reacts Wherein: n is same as described above, and L representation hydroxy, halogen or acetoxyl group.
Preferred Trimethylhydroquinone diacetate esters and the isophytol of using is as reactant.This diacetate esters is particularly suitable for preparing according to the method for EP-A0808815.
In a preferred embodiment, introduce ester and the zinc halide and the acid of the logical formula II of dissolved at first together, in this solution, add the compound of logical formula III or (IV) then.The water and the acetate that form in the reaction remain in the reaction mixture, and do not remove.
Exceed that those of ordinary skills are unexpected to be,, still can make desirable ester with high density although acidic medium is arranged and exist as the water of product.After the reaction, randomly use known method, particularly carry out acetylize, nonesterified compound is converted into desirable ester with diacetyl oxide.
A kind of verifiedly is that the TMHQ diacetate esters with respect to introducing is set in 10 with the water concentration in the reaction mixture for special effective means -2Mol%-100mol%.This can realize by quantitative interpolation protonic acid aqueous solution or concentrated protonic acid.The productive rate that can obtain when using hydrochloric acid as protonic acid.Other suitable acid can be sulfuric acid, has various SO 3Sulfuric acid/the SO of concentration 3Mixture, trifluoromethanesulfonic acid and H 0Value is less than or equal to-11.9 corresponding peracid, particularly boric acid and the mixture of oxalic acid, and their mol ratio is generally 1: 1-1: 5, particularly 1: 2.With respect to the TMHQ diacetate esters, their working concentration is generally 10 -2-100mol%.
With respect to the Trimethylhydroquinone diacetate esters, the working concentration of zinc halide, particularly zinc chloride or zinc bromide is in particular 10-100mol%.
Though the usage quantity to solvent is not specifically limited, preferably use the 0.1-100ml/gTMHQ diacetate esters, wherein 1-10ml/g is specially suitable.
In a preferred embodiment, at first introduce the initiator that leads to formula II, catalyst mixture and the organic solvent that comprises Lewis acid and Br nsted acid, add compound then according to logical formula III or (IV).After the reaction, separate desirable product, and randomly use currently known methods to carry out esterification.
The organic solvent that is applicable to this reaction is a carbonic ether, as methylcarbonate, diethyl carbonate, dipropyl carbonate, Methyl ethyl carbonate, NSC 11801 and propylene carbonate, perhaps carboxylicesters is as n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert.-butyl acetate, n-amyl acetate, Isoamyl Acetate FCC [CH 3COOCH 2CH 2CH (CH 3) 2], sec-amyl acetate [CH 3COOCH (CH 3) (CH 2) 2CH 3], tert.-amyl acetate [CH 3COOC (CH 3) 2CH 2CH 3], acetate 2,2-dimethyl propyl ester [CH 3COOCH 2C (CH 3) 3], acetate 2-methyl butyl ester [CH 3COOCH 2CH (CH 3) CH 2CH 3], methyl propionate, n-butyl propionate, ethyl butyrate, isopropyl butyrate, methyl isobutyrate, ethyl isobutyrate, isobutyl isobutyrate, methyl valerate, Valeric acid ethylester, methyl isovalerate, Ethylisovalerate.Wherein, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, n-butyl propionate, ethyl butyrate, isopropyl butyrate, methyl isobutyrate, ethyl isobutyrate, methyl valerate are specially suitable.
This organic solvent also can be non-polar solvent, as pentane, hexane, heptane, octane, petroleum naphtha, sherwood oil, hexanaphthene, benzene, toluene and dimethylbenzene, it perhaps is fatty alcohol, as methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, Pentyl alcohol (1-amylalcohol), 2-amylalcohol (1-methyl isophthalic acid-butanols), 3-amylalcohol (1-ethyl-1-propanol), primary isoamyl alcohol (3-methyl isophthalic acid-butanols), tertiary amyl alcohol (1,1-dimethyl-1-propyl alcohol), 2,2-dimethyl-1-propyl alcohol, 1,2-dimethyl-1-propyl alcohol, the pure and mild 3-methyl of 2-methyl-1-butene-2-butanols.Wherein particularly preferably be the mixture of n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, Pentyl alcohol, 2-amylalcohol, 3-amylalcohol, primary isoamyl alcohol and tertiary amyl alcohol and above-mentioned solvent.In solvent mixture, wherein a kind of solvent can be used as cosolvent.
In addition, use, selectivity is had special influence as the cyclic carbonate ester of NSC 11801 or propylene carbonate and open chain ester such as ethyl acetate, propyl acetate, butylacetate and the isobutyl acetate of acetate.
Also can in liquid or supercritical carbon dioxide solvent, carry out ring-closing condensation reaction.And can stop proceeding of reaction, and reclaim the catalyzer in the appropriate solvent without any material.
According to the present invention, in the presence of protonic acid and zinc halide, outside being all beyond one's expectations by synthetic simply DL-alpha-tocopherol of the compound of describing in detail in Trimethylhydroquinone two or monoacetate and isophytol or the claim 1 or DL-alpha-tocopherol acetate, this is that during reaction the condensation water of Xing Chenging will be removed from reaction system usually because according to prior art.But on the contrary, in the method for the invention, water plays catalytic effect, and if optionally react, this water still is necessary.
Find also that in addition method of the present invention has been simplified ordinary method widely, unlike the prior art, use the TMHQ of esterification, and ester group wherein obtains keeping with unhoped-for degree in the final product of logical formula I.Therefore, in acetylize subsequently, saved diacetyl oxide.
On the other hand, go back the crude product of sponifiable reaction, to form DL-alpha-tocopherol as final product.
Therefore, but proved the economic means that the VITAMIN E ACETATE synthesis method can be converted into industrial application, it has reduced reactions steps, and has reduced the cost of raw material.
α-DL-the VITAMIN E ACETATE of embodiment 1 synthetic following formula:
Figure A9812568600101
Will be at the 10.9g in 15ml hexane, 0.7ml propyl carbinol and the 15ml n-propyl acetate (=46mmol) Trimethylhydroquinone 1,4-diacetate esters (GC:100%), 5.2g (=38.17mmol=83mol% is with respect to TMHQ-DA) ZnCl 2Be heated to 60 ℃ with the 0.65ml concentrated hydrochloric acid.In inherent this solution of times of 4 hours, drip 14.5g (=48mmol) isophytol (GC:＞98%).After interpolation is finished, continue down to stir 2 hours at 60 ℃.After reaction is finished, immediately mixture is cooled to room temperature, and in the gained reaction mixture, adds the 100ml sherwood oil.Wash above-mentioned solution with 2 * 20ml water and 2 * 20ml saturated sodium bicarbonate solution.Separate organic phase, dry on sal epsom, and after the filter salts in rotatory evaporator extraction solvent.Obtain the 21g yellow oil, analyze, this oily matter composed as follows according to HPLC: the 28wt% vitamin-E (=5.88g), the 65.8wt% vitamin e acetate (=13.82g), 1.6wt% (=0.34g) TMHQ monoacetate.After free vitamin E composition is converted into the vitamin e acetate equivalent, find that the overall yield of VITAMIN E ACETATE is 20.27g, be equivalent to 93.2% of theoretical value.The transformation efficiency of TMHQ diacetate esters is quantitative.Embodiment 2 is from TMHQ-DA synthetic tocopherol acetic ester
Use the method identical, and in the 15ml isobutyl acetate, at first introduce 10.9g (=46mmol) TMHQ diacetate esters with embodiment 1.In this solution, add 0.63ml concentrated hydrochloric acid and 5.2g (=38.17mmol) ZnCl 2In 6 hours time, add isophytol (14.5g=48mmol) down in 60 ℃.After the conventional processing, obtain the brown crude product of 21.7g, analyze according to HPLC, this crude product has following composition: 37.6wt% tocopherol and 54.5wt% VITAMIN E ACETATE.The transformation efficiency of TMHQ diacetate esters is 100%, but still finds the TMHQ-MA of 0.74wt%.This productive rate that is equivalent to vitamin e acetate is 11.8g, and the productive rate of vitamin-E is 8.16g.After vitamin-E was converted into vitamin e acetate, this was equivalent to 95.45% productive rate.The TMHQ-MA transformation efficiency is 98.17% o'clock, and the selectivity of vitamin-E is 42%.The selectivity of vitamin e acetate is 55.3%.The overall selectivity of desired product is 97.3%.Embodiment 3 is by TMHQ-MA synthetic tocopherol acetic ester
Use the method identical, but do not use diacetate esters, and be to use the TMHQ monoacetate that obtains by the selectivity saponification reaction with embodiment 1.In the 15ml ethyl acetate, at first introduce 5.2g (38.17mmol) ZnCl 2And 8.9g (=45.8mmol) TMHQ monoacetate adds the 0.63ml concentrated hydrochloric acid then in this mixture, and with mixture heating up to 60 ℃.Continuous dropping isophytol 13.8g in 2.5 hours time (=46.5mmol).Make to be reflected at and proceed 2.5 hours under 50 ℃.After the conventional processing, obtain brown oil, analyze according to HPLC, this oily matter has following composition: 4.83wt%TMHQ-MA, 18wt% vitamin-E and 66.9wt% vitamin e acetate.Final weight is 21.0g.This is equivalent to productive rate is 84%.Transformation efficiency is 88.6%, and the selectivity of tocopherol and VITAMIN E ACETATE is 94.8%.Embodiment 4 is by TMHQ-DA synthetic tocopherol acetic ester
The interpolation order of component is identical with embodiment 1, at first introduces 5.2g (38.17mmol) ZnCl in the 15ml n-propyl acetate 2, 0.65ml concentrated hydrochloric acid and 10.9g (=46.1mmol) TMHQ-DA.Then in 4.5 hours time in 50 ℃ add down isophytol 14.5g (=48.9mmol), and continue to stir 1.5 hours.After the conventional processing, obtain 19.3g Honey color oily matter, analyze according to HPLC, this oily matter has following composition: 15.8wt% vitamin-E and 64.5wt% vitamin e acetate.After formed vitamin-E composition was converted into the vitamin e acetate of equivalent, being equivalent to productive rate was 72.5%.Embodiment 5 synthetic alpha-tocopherol acetic ester
Use the method identical with embodiment 4, the additive of identical stoichiometry, but use the 15ml isobutyl acetate to replace n-propyl acetate as solvent, and in mixture the water of interpolation 0.83ml.With identical method treating mixture, obtain the product of light brown oily thing in reaction under 50 ℃ after 6 hours, analyze according to HPLC, this oily matter has following composition: 20.1wt% vitamin-E and 67.71wt% vitamin e acetate.The content that detects corresponding monoacetate is 2.0wt%.Therefore, productive rate is 90% of a theoretical value.Embodiment 6 is by alpha-tocopherol acetate
Use the method identical, and in the 15ml methyl iso-butyl ketone (MIBK), at first introduce 5.2g (=38.17mmol) ZnCl with embodiment 4 2And 8.9g (=45.8mmol) TMHQ monoacetate adds the 0.63ml concentrated hydrochloric acid then in this mixture, and with mixture heating up to 35-40 ℃.Keep this temperature, and in 2.5 hours time, add isophytol 13.8g (=46.5mmol), continue then to stir 2.5 hours.After the cooling, with 10ml water washing mixture.In organic phase, add 60ml toluene, wash this mixture, then wash again with 20ml water with 20ml 2% sodium hydroxide solution, drying, and on rotatory evaporator, evaporate at last.Obtain 19.1g brown syrup sample oily matter, analyze according to quantitative HPLC, this oily matter has the alpha-tocopherol acetate that content is 47.7wt%.This is equivalent to productive rate is 42.1%.At transformation efficiency is 85.4% o'clock, and TMHQ-MA is 49.3% to the selectivity of VITAMIN E ACETATE.Only detect the free tocopherol of trace.Embodiment 7 is by TMHQ-MA synthetic alpha-tocopherol acetic ester
Use the method identical, and in the 15ml methyl iso-butyl ketone (MIBK), at first introduce 5.2g (38.17mmol) ZnCl with embodiment 4 2And 8.9g (=45.8mmol) TMHQ monoacetate adds the 0.63ml concentrated hydrochloric acid then in this mixture, and with mixture heating up to 50 ℃.Keep this temperature, and in 2.5 hours time, add isophytol 13.8g (=46.5mmol), continue to stir 2.5 hours.After the cooling, with 10ml water washing mixture.Add 60ml toluene in organic phase, with 20ml 2% sodium hydroxide solution purging compound, wash with 20ml water then again, drying is evaporated in rotatory evaporator at last.Obtain 21.7g brown syrup sample oily matter, according to the HPLC quantitative analysis, the content of alpha-tocopherol is 13.15wt% in this oily matter, and the content of VITAMIN E ACETATE is 80.42wt%.After the vitamin-E composition was converted into corresponding vitamin e acetate equivalent, productive rate was 20.58g or 95.1%.Embodiment 8 is by TMHQ-DA synthetic alpha-tocopherol acetic ester
Use the method identical, but do not use concentrated hydrochloric acid, but during reaction hydrogen chloride gas is introduced in the reaction soln continuously, and use water separator, from system, to remove the water of dereaction formation as protonic acid with embodiment 1.At first with 9.2g (=67.5mmol=68.4mol% is with respect to TMHQ-DA) ZnCl 2And 23.6g (=98.62mmol) the TMHQ diacetate esters is introduced in the 100ml toluene, adds 0.17g octadecane amine in this mixture, then with mixture heating up to reflux temperature.Keep this temperature, and quantitatively adding 29.6g (=99.8mmol) isophytol, and continuation stirring 2.5 hours in 2.5 hours time.During adding isophytol and after the reaction, in reaction soln, introduce hydrogenchloride.Cooling mixture is dissolved in crude mixture in the 400ml sherwood oil again, and washs in proper order routinely with the water and the sodium hydrogen carbonate solution of appropriate amount.Evaporation gained organic phase in rotatory evaporator.Obtain 41.0g brown syrup sample oily matter.According to the HPLC quantitative analysis, this oily matter comprises the 2.9wt% alpha-tocopherol, and the content of VITAMIN E ACETATE is 69.5wt%.After the vitamin-E composition was converted into corresponding vitamin e acetate equivalent, productive rate was 29.8g or 63.9%.Comparative Examples 1 (according to EP0694541) is from the TMHQ synthetic alpha-tocopherol
Use the method for describing in this patent, and (=153mmol) TMHQ and the 17.5g (=129mmol) ZnCl that at first in the 54ml methyl isobutyl ketone solvent, introduces 23.3g 2With the 2.2ml concentrated hydrochloric acid.In 3 hours time, add 46.1g (=153mmol) isophytol at above-mentioned solution.Temperature of reaction is 25-30 ℃, and the reaction times is 5 hours.After the conventional processing, obtain brown oily end product, final weight is 61.8g.According to the HPLC quantitative analysis, the content of alpha-tocopherol is 91.4wt% in this oily matter.This is 78.1% corresponding to productive rate.Embodiment 9-13 synthetic alpha-tocopherol acetic ester
Carry out following experiment, with of the influence of investigation cosolvent to heptane solvent.Use the method for describing among the embodiment 1, but use concentrated hydrobromic acid, from system, do not remove water or acetate that condensation reaction forms as protonic acid.At first in the 10ml heptane, introduce 8.6g (=38.2mmol=82.9mol% is with respect to TMHQ-DA) ZnBr 2And 10.9g (=46.1mmol) TMHQ diacetate esters.According to experiment, add the concrete alcohol of 1ml as cosolvent.Adding 1.3ml 47% Hydrogen bromide in described mixture (=11.49mmol=24.9mol%).Then in 1.5 hours time, adding 105mol% (=14.5g=48.9mmol) isophytol under 60 ℃.Keep this temperature, and continue to stir 2 hours.Cooling mixture carries out conventional processing.Following table has shown the productive rate and the content of vitamin-E and vitamin e acetate in a series of experiments.
Cosolvent Final weight (g) Content of vitamin E (wt%) VE acetate content (wt%) Overall yield (% of theoretical value)
?/ ????20.9 ????40.3 ????53.2 ????93.9
Propyl carbinol ????21.5 ????45.5 ????49.2 ????97.8
The 1-amylalcohol ????22.6 ????32.5 ????60.7 ????93.9
The 2-amylalcohol ????22.2 ????23.3 ????66.0 ????93.2
The 3-amylalcohol ????23.0 ????19.4 ????68.4 ????94.6
Embodiment 14-21 synthetic alpha-tocopherol acetic ester
Carry out following experiment, with investigation ZnCl 2The influence of concentration.Use the method for describing among the embodiment 1, but use concentrated hydrochloric acid, and from system, do not remove water or the acetate that condensation reaction forms as protonic acid.At first in the acetate isobutyl, introduce the zinc chloride measured shown in the following table and 10.9g (=46.1mmol) TMHQ diacetate esters.37% hydrochloric acid that in this mixture, adds 0.63ml.In in 4.0 hours time, adding 105mol% (=14.5g=48.9mmol) isophytol under 60 ℃.Keep this temperature, and continue to stir 2 hours.Cooling mixture, and carry out conventional processing.Following table shown-serial experiment in productive rate and the content of vitamin-E and vitamin e acetate.
ZnCl 2Amount (mol%) ZnCl 2Amount (g) The ratio of VE/VE-Ac VE content (wt%) VE acetate content (wt%) Final weight (g) * Transformation efficiency (%) Productive rate **
????0.0 ?0.0 ?99∶1 ?8.3 ?0.14 ?17.4 ?28.5 ?7.4
????15.9 ?1.0 ?23∶77 ?14.7 ?53.9 ?22.6 ?81 ?72.6
????25.4 ?1.6 ?35∶65 ?25.6 ?65.2 ?21.0 ?98.3 ?85.4
????41.4 ?2.6 ?33∶67 ?28 ?62.3 ?21.3 ?97.3 ?91.0
????51 ?3.2 ?31∶69 ?25.9 ?61.8 ?21.2 ?97.3 ?92.5
????63.5 ?4.0 ?34∶66 ?28.9 ?61.7 ?22.1 ?99.0 ?94.8
????82.9 ?5.2 ?43∶57 ?37.6 ?54.4 ?21.7 ?99.3 ?95.4
????100 ?6.3 ?28∶72 ?22.1 ?62.5 ?21.8 ?98.3 ?98.3
* crude product is formed * * for determining productive rate by THMQ-DA, TMHQ-MA, vitamin-E and vitamin e acetate, and the vitamin-E composition is converted into the vitamin e acetate equivalent.Standard test: 10.9g TMHQ-DA (100%)=46.1mmol
14.5g isophytol (BASF:GC:＞98%)=48.9mol
Protonic acid: 0.63ml concentrated hydrochloric acid
Lewis acid: the Xg zinc chloride, temperature: 60 ℃, the reaction times: 6 hours embodiment 22-28 synthetic alpha-tocopherol acetic ester
Carry out following experiment, with investigation ZnBr 2The influence of concentration.Use the method for describing among the embodiment 14-21, but use concentrated hydrobromic acid as protonic acid.From system, do not remove water or acetate that condensation reaction forms.At first in the mixed solvent of heptane and butanols, introduce the zinc bromide measured shown in the following table and 10.9g (=46.1mmol) TMHQ diacetate esters.47% Hydrogen bromide that in this mixture, adds 0.63ml.In in 2.0 hours time, adding 105mol% (=14.5g=48.9mmol) isophytol under 60 ℃.Keep this temperature, and continue to stir 2 hours.Cooling mixture, and carry out conventional processing.Following table has shown the productive rate and the content of vitamin-E and vitamin e acetate in a series of experiments.
ZnBr 2Amount (mol.%) ZnBr 2Amount (g) The ratio of VE/VE-Ac VE content (wt.%) VE acetate content (wt.%) Final weight (g) * Transformation efficiency (%) Productive rate **
????10 ?1.04 ?32∶68 ?19.34 ?44.24 ?22.5 ?97.4 ?67.6
????20 ?2.08 ?31∶69 ?25.57 ?63.71 ?22.2 ?99.3 ?93.5
????30 ?3.11 ?37∶63 ?31.92 ?58.62 ?22.1 ?100 ?94.9
????40 ?4.16 ?44∶56 ?37.66 ?53.62 ?21.6 ?100 ?93.6
????60 ?6.22 ?30∶70 ?25.98 ?66.0 ?21.5 ?100 ?93.2
????80 ?8.32 ?36∶64 ?30.85 ?60.2 ?22.2 ?100 ?95.8
????100 ?10.38 ?40∶60 ?34.31 ?55.41 ?22.1 ?100 ?94.3
* crude product is formed * * for determining productive rate by THMQ-DA, TMHQ-MA, vitamin-E and vitamin e acetate, and the vitamin-E composition is converted into the vitamin e acetate equivalent.Standard test: 10.9g TMHQ-DA (100%)=46.1mmol
14.5g isophytol (BASF:GC:＞98%)=48.9mmol
Protonic acid: 0.63ml concentrated hydrobromic acid
Lewis acid: the Xg zinc bromide, temperature: 60 ℃, the reaction times: 4 hours
Solvent: 15ml heptane, 1.5ml n-propyl alcohol embodiment 29-38 alpha-tocopherol acetate synthetic
Carry out following experiment, with the influence of investigation at zinc bromide protonic acid property when acid exists as Lewis.In this investigation, comprise mineral acid and organic acid.Following experimentizing: at first introduce TMHQ-DA in the butanols as cosolvent, add the aqueous acid of appropriate amount then and as the zinc bromide of Lewis acid at 15ml heptane and 1.5ml.In water-bath,, behind initial 15 minutes, in 3 hours time, add isophytol continuously with mixture heating up to 60 ℃.After carrying out reaction in 3 hours again, mixture is carried out conventional processing.Following table has shown productive rate and the transformation efficiency that obtains thus.
Lewis acid The protonic acid type Concentration (mol%) Water concentration (mol%) Productive rate (%) ** Transformation efficiency (%) VE/VE-Ac (mol ratio)
?ZnBr 2 Concentrated hydrochloric acid (=37%) ????25 ?86 (=0.95ml) ????91.7 ????99.9 ????48∶52
?ZnBr 2 Concentrated hydrobromic acid (=47%) ????25 ?126 (=1.35ml) ????92.2 ????99.8 ????51∶49
?ZnBr 2 Dense hydroiodic acid HI (=57%) ????25 ?134 (=1.52ml) ????91.7 ????99.9 ????50∶50
?ZnBr2 ?H 2SO 4(=30％) ????25 ?319 (=3.1ml) ????92.9 ????99 ????60∶40
?ZnBr 2 ?H 2SO 4(=60％) ????25 ?91 ?(=1.26ml) ????89.5 ????99.8 ????47∶53
?ZnBr 2 ?NaHSO 4(=70％) ????25 ?86 (=2.29g) ????79.4 ????98.4 ????22∶78
?ZnBr 2 ?CF 3SO 3H (=30％) ????25 ?482 (=5ml) ????83.8 ????98.9 ????44∶56
?ZnBr 2 ?Cl 3CO 2H (=70％) ????25 ?96 (=2.68g) ????32.2 ????69.6 ????2∶98
?ZnBr 2 ?Cl 3CO 2H (=100％) ????50 ?0 (=3.77g) ????41.2 ????71.5 ????3∶97
?ZnBr 2 ?H 3PO 4(=60％) ????25 ?91 (=1.32ml) ????68.2 ????88.6 ????29∶71
* in the TMHQ-DA of introducing, the numeral in the bracket is relevant with the aqueous acid of introducing; The productive rate (before distillation) that * calculates with total vitamin e acetate.Standard test: 10.9g TMHQ-DA (100%)=46.1mmol
The 15ml heptane, the ultrapure butanols of 1ml
8.6g?ZnBr 2(=38.2mmol=82.9mol％)
14.5g isophytol (BASF:GC:＞98%)=48.9mmol
Temperature of reaction: 60 ℃ of embodiment 39/40 alpha-tocopherol acetates synthetic
At first in the propylene carbonate of appropriate amount, introduce TMHQ-DA, Lewis acid and protonic acid.In water-bath,, behind initial 15 minutes, in 3 hours time, add isophytol continuously with mixture heating up to 60 ℃.In this serial experiment, the stoichiometric ratio of TMHQ-DA/ isophytol is 3: 1.The amount of solvent changes.After carrying out reaction in 3 hours again, with petroleum ether extraction propylene carbonate phase.Analyze two phases.Reuse the unreacted TMHQ ester of propylene carbonate in mutually.Following table has shown productive rate and the transformation efficiency that obtains thus.
Solvent (ml) 20 ?60
?ZnCl 2(mol％) 40 ?40
?H +Concentration (mol%) ** 25 ?25
Water concentration (mol%) 85(=0.7ml ?85(=0.7ml
Productive rate (%) *** 89.9 ?80.2
IP transformation efficiency (%) 100 ?100
The TMHQ ester that retains 92 ?89
VE/VE-Ac (mol ratio) 3∶97 ?3∶97
* the isophytol to introduce; * is with respect to the Br nsted acid concentration of isophytol; The productive rate (before distillation) that * * calculates with total vitamin e acetate.Initial weight: 32.7g=138mmol TMHQ-DA;
13.8g=46mmol?IP；
2.5gZnCl 2(=18.4mmol=82.9mol%); 1.12ml concentrated hydrochloric acid embodiment 41-45 alpha-tocopherol acetate is synthetic
At first in propylene carbonate, introduce TMHQ-DA, Lewis acid and protonic acid.In water-bath,, behind initial 15 minutes, in 3 hours time, add isophytol continuously with mixture heating up to 60 ℃.In this serial experiment, with respect to TMHQ-DA, the excessive 5mol% of isophytol.After carrying out reaction in 3 hours again, with petroleum ether extraction propylene carbonate phase.Described productive rate is disregarded at vitamin-E or the vitamin e acetate of propylene carbonate in mutually.Following table has shown productive rate and the transformation efficiency that obtains thus.
????ZnCl 2????(mol％) ????H +Concentration (mol%) * Temperature (℃) Productive rate (%) ** IP transformation efficiency (%) VE/VE-Ac (mol ratio)
????40 ????25 ????60 ????81.54 ????100 ????52∶48
????40 ????25 ????100 ????78.4 ????100 ????85∶15
????40 ????12.5 ????60 ????78.4 ????100 ????39∶61
????40 ????12.5 ????80 ????79.8 ????100 ????54∶46
????40 ????12.5 ????100 ????75.2 ????100 ????68∶32
* with respect to the Br nsted acid concentration of TMHQ-DA; The productive rate (before distillation) that * calculates with total vitamin e acetate is in TMHQ-DA.Initial weight: 10.9g=46mmol TMHQ-DA;
14.75g=49mmol?IP；
2.5g?ZnCl 2(=18.4mmol=82.9mol％)；
0.62g?H 2O(=75mol％H 2O)；
H +Calculating=H 3BO 3/ C 2O 4H 2Synthesizing of (mol ratio 1: 2)=12.5-25mol% embodiment 46-51 alpha-tocopherol acetate
Carry out following experiment, with the influence of investigation in zinc bromide water concentration and Br nsted acid concentration when acid exists as Lewis.Following experimentizing: at first introduce TMHQ-DA in the butanols as cosolvent, add the aqueous acid of appropriate amount then and as the zinc bromide of Lewis acid at 15ml heptane and 1.5ml.In water-bath,, behind initial 15 minutes, in 3 hours time, add isophytol continuously with mixture heating up to 60 ℃.After carrying out reaction in 3 hours again, mixture is carried out conventional processing.Following table has shown productive rate and the transformation efficiency that obtains thus.
Lewis acid (mol%) The type of protonic acid Concentration (mol%) * Water concentration (mol.%) ** Productive rate (%) *** Transformation efficiency VE/VE-Ac (mol ratio)
????ZnBr 2????(82.9) CF 3SO 3H ????25 ????482 ????83.8 ????98.9 ????44∶56
????ZnBr 2????(82.9) CF 3SO 3H ????25 ????96 ????94.5 ????100 ????45∶55
????ZnBr 2????(82.9) CF 3SO 3H ????10 ????96 ????97.1 ????100 ????46∶54
????ZnBr 2????(82.9) CF 3SO 3H ????10 ????48 ????90.1 ????100 ????29∶71
????ZnBr 2????(82.9) CF 3SO 3H ????5 ????96 ????82.7 ????97.3 ????15∶85
????ZnBr 2????(82.9) CF 3SO 3H ????5 ????48 ????80.6 ????97.1 ????17∶83
* in the TMHQ-DA of introducing, the numeral in the bracket is relevant with the aqueous acid of introducing; The TMHQ-DA of * to introduce; The productive rate (before distillation) that * * calculates with total vitamin e acetate.Standard test: 10.9g TMHQ-DA (100%)=46.1mmol
The 15ml heptane, the ultrapure butanols of 1ml
8.6g?ZnBr 2(=38.2mmol=82.9mol％)
14.5g isophytol (BASF:GC:＞98%)=48.9mmol Comparative Examples 2 according to JP-OS Sho 51-80859 at 125 ℃ of following preparation DL-alpha-tocopherol acetates
At first will the 15.5g in the 20ml butylacetate (=65.6mmol) TMHQ-DA and 12.0g (=88mmol) zinc chloride is introduced in the 200ml three-necked flask, this flask is equipped with agitator, reflux exchanger, thermometer and dropping funnel.The gained mixture refluxes under nitrogen gas stream, and wherein reflux temperature is 125 ℃.Be dissolved in 37.7g in the other 10ml butylacetate (=127.3mmol) isophytol dropped in the described boiling mixture in 50 minutes.Be reflected under the backflow and proceed 4 hours.After reaction is finished, water extractive reaction mixture immediately, wherein zinc chloride enters water, and tocopherol/VITAMIN E ACETATE mixture is still stayed in the organic phase.According to gas chromatographic analysis, TMHQ-DA transforms fully, and the thick productive rate of tocopherol is 22.5%, and the productive rate of VITAMIN E ACETATE is 45.8%, and with respect to TMHQ-DA, the overall yield of tocopherol/VITAMIN E ACETATE is 68%.Comparative Examples 3 prepares DL-alpha-tocopherol acetate (catalyzer=ZnCl according to JP-OS Sho 51-80859 down at 60 ℃ 2, no protonic acid)
That describes in method and the Comparative Examples 1 is identical, but temperature of reaction is reduced to 60 ℃.After handling routinely, gas chromatographic analysis is carried out in the organic composition of mixture, 100% initiator TMHQ-DA is recovered.Therefore, be reflected under this condition and do not carry out.

Claims (10)

1, a kind of method for preparing alpha-tocopherol esters, its derivative or the analogue of following logical formula I,
Figure A9812568600021
The method is characterized in that,, under 25-100 ℃, make the quinhydrones monoesters or the diester of logical formula II at zinc halide with when releasing protonic acid and existing
Figure A9812568600022
Wherein: R 1, R 2Represent branch or not branched, saturated or undersaturated C 1-C 20Alkyl,
R 3, R 4, R 5Represent H, C 1-C 3Alkyl, their allyl alcohol derivative reactions identical or different and logical formula III,
Figure A9812568600031
Wherein: n represents the number of 0-5, and L representation hydroxy, halogen, acetoxyl group, mesyloxy, ethanesulfonyloxy group, phenylsulfonyloxy or tosyl group, perhaps the vinyl carbinol with logical formula IV reacts Wherein: n is same as described above, and L representation hydroxy, halogen or acetoxyl group.
2, the method for claim 1 is characterized in that, in TMHQ diester, particularly diacetate esters, is having 10 -2-100mol% reacts during zinc halide.
As claim 1 and 2 described methods, it is characterized in that 3, described protonic acid is the mixture of hydrochloric acid or Hydrogen bromide or sulfuric acid or trifluoromethanesulfonic acid or boric acid and oxalic acid.
As the described method of claim 1-3, it is characterized in that 4, in the TMHQ diacetate esters, the working concentration of protonic acid is 1-100mol%.
5, as the described method of claim 1-4, it is characterized in that, use 0.1-100ml solvent/g TMHQ diacetate esters, particularly 1-10ml/g.
As the described method of claim 1-5, it is characterized in that 6, solvent for use is the ring or the aliphatic carbonate of C-1 to C-4 carbochain alcohol, perhaps carboxylicesters or non-polar solvent such as aliphatic hydrocrbon or aromatic hydrocarbon.
As the described method of claim 1-6, it is characterized in that 7, the reaction mol ratio of TMHQ diacetate esters and isophytol is 1: 1-10: 1.
8, as the described method of claim 1-7, it is characterized in that reaction is carried out continuously.
As the described method of claim 1-8, it is characterized in that 9, the reaction water that forms between the reaction period to small part remains in the reaction mixture.
10, as the described method of claim 1-9, it is characterized in that, at first in solvent, introduce ester, zinc halide and the protonic acid of logical formula II, in this mixture, add the compound of logical formula III or (IV) then.
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CN105418574A (en) * 2014-08-27 2016-03-23 浙江医药股份有限公司新昌制药厂 dl-alpha tocopherol acetate preparation method
CN113083339A (en) * 2021-04-15 2021-07-09 万华化学(四川)有限公司 Catalyst for preparing vitamin E and preparation method and application thereof
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DE19951006A1 (en) * 1999-10-22 2001-04-26 Degussa Process for the preparation of esterified chroman compounds
DE10011402A1 (en) * 2000-03-09 2001-09-13 Degussa Process for the preparation of alpha-tocopherol esters
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KR100533304B1 (en) * 2001-05-26 2005-12-05 주식회사 엘지생명과학 Polyethoxylated alpha tocopherol ester derivatives and process for preparing the same
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EP1562929B1 (en) * 2002-11-21 2007-11-14 DSM IP Assets B.V. Manufacture of tocopheryl acetate
CN116535377B (en) * 2023-05-04 2025-06-10 山东新和成精化科技有限公司 A kind of preparation process of vitamin E acetate
WO2025242782A1 (en) * 2024-05-23 2025-11-27 Dsm Ip Assets B.V. Mono-saponifaction of diesters of trimethylhydroquinone and its use in the process of manufacturing esterified alpha-tocopherol

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CN100344621C (en) * 2003-01-13 2007-10-24 帝斯曼知识产权资产管理有限公司 Process for the manufacture of alpha-tocopheryl acetate
CN105418574A (en) * 2014-08-27 2016-03-23 浙江医药股份有限公司新昌制药厂 dl-alpha tocopherol acetate preparation method
CN113083339A (en) * 2021-04-15 2021-07-09 万华化学(四川)有限公司 Catalyst for preparing vitamin E and preparation method and application thereof
CN113083339B (en) * 2021-04-15 2022-11-08 万华化学(四川)有限公司 Catalyst for preparing vitamin E and preparation method and application thereof
CN116730804A (en) * 2023-02-23 2023-09-12 吉林北沙制药有限公司 A method for recycling and reusing 2,3,6-trimethylhydroquinone diacetate

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